It has been shown through the study of three kinds of carcinoma that the progeny of malignant stem cells have the capacity for differentiation, yielding benign and, in one case, normal progeny. Direction of this naturally occurring differentiation of tumors could serve as an alternative to cytotoxic therapy. To this end, a multidisciplinary approach to the study of differentiation in tumors will be mounted. It will include inputs from experimental pathologists, cell biologists, molecular biologists, biochemists, and developmental biologists. Focus will be on three essential processes: the environment of differentiating cells, the plasma cell membrane which must mediate environmental signals, and finally, the way neoplastic genomes are controlled. Specifically, we will study control of genomes through the study of the synthesis of the transforming protein encoded for in the src region of RNA tumor viruses. Membrane studies will include molecular studies of transbridging proteins and comparisons of the metabolisms of normal and neoplastic membranes including the distribution and turnover of glycoproteins, and effects of growth promoters on membranes. Comparisons will be made of asymmetrical distribution of proteins of membranes of karyoplasts and nucleoplasts of normal and malignant cells to obtain information on cell-cell interactions. Comparison will be made of the effects of DNA tumor viruses on differentiation of cells or early embryos and of teratocarcinomas. Flow microfluorimetry will be done on temperature-sensitive mutants of SV40 to determine the mechanism of action. The role of embryonic fields in directing differentiation of neoplastic cells will be studied. Functional differentiation in developing pituitary glands, pituitary tumors, and in liver cells will be studied.